Targeted rescue of a polycystic kidney disease mutation by lysosomal inhibition.
Identifieur interne : 000215 ( PubMed/Corpus ); précédent : 000214; suivant : 000216Targeted rescue of a polycystic kidney disease mutation by lysosomal inhibition.
Auteurs : Alexis Hofherr ; Claudius J. Wagner ; Terry Watnick ; Michael KöttgenSource :
- Kidney international [ 1523-1755 ] ; 2016.
English descriptors
- KwdEn :
- Animals, Antirheumatic Agents (pharmacology), Antirheumatic Agents (therapeutic use), Chloroquine (pharmacology), Chloroquine (therapeutic use), Drosophila melanogaster, Drug Evaluation, Preclinical, Female, HEK293 Cells, HeLa Cells, Humans, Lysosomes (drug effects), Lysosomes (metabolism), Male, Mutation, Missense, Polycystic Kidney, Autosomal Dominant (drug therapy), Polycystic Kidney, Autosomal Dominant (genetics), Polycystic Kidney, Autosomal Dominant (metabolism), Protein Stability, TRPP Cation Channels (genetics), TRPP Cation Channels (metabolism).
- MESH :
- chemical , genetics : TRPP Cation Channels.
- chemical , metabolism : TRPP Cation Channels.
- chemical , pharmacology : Antirheumatic Agents, Chloroquine.
- chemical , therapeutic use : Antirheumatic Agents, Chloroquine.
- drug effects : Lysosomes.
- drug therapy : Polycystic Kidney, Autosomal Dominant.
- genetics : Polycystic Kidney, Autosomal Dominant.
- metabolism : Lysosomes, Polycystic Kidney, Autosomal Dominant.
- Animals, Drosophila melanogaster, Drug Evaluation, Preclinical, Female, HEK293 Cells, HeLa Cells, Humans, Male, Mutation, Missense, Protein Stability.
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal disease. The molecular pathogenesis of ADPKD is not completely known, and there is no approved therapy. To date, there is limited knowledge concerning the molecular consequences of specific disease-causing mutations. Here we show that the ADPKD missense variant TRPP2(D511V) greatly reduces TRPP2 protein stability, and that TRPP2(D511V) function can be rescued in vivo by small molecules targeting the TRPP2 degradation pathway. Expression of the TRPP2(D511V) protein was significantly reduced compared to wild-type TRPP2. Inhibition of lysosomal degradation of TRPP2(D511V) by the US Food and Drug Administration (FDA)-approved drug chloroquine strongly increased TRPP2 protein levels in vitro. The validation of these results in vivo requires appropriate animal models. However, there are currently no mouse models harboring human PKD2 missense mutations, and screening for chemical rescue of patient mutations in rodent models is time-consuming and expensive. Therefore, we developed a Drosophila melanogaster model expressing the ortholog of TRPP2(D511V) to test chemical rescue of mutant TRPP2 in vivo. Notably, chloroquine was sufficient to improve the phenotype of flies expressing mutant TRPP2. Thus, this proof-of-concept study highlights the potential of directed therapeutic approaches for ADPKD, and provides a rapid-throughput experimental model to screen PKD2 patient mutations and small molecules in vivo.
DOI: 10.1016/j.kint.2015.11.015
PubMed: 26924047
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Targeted rescue of a polycystic kidney disease mutation by lysosomal inhibition.</title><author><name sortKey="Hofherr, Alexis" sort="Hofherr, Alexis" uniqKey="Hofherr A" first="Alexis" last="Hofherr">Alexis Hofherr</name><affiliation><nlm:affiliation>Renal Division, Department of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. Electronic address: alexis.hofherr@uniklinik-freiburg.de.</nlm:affiliation></affiliation></author><author><name sortKey="Wagner, Claudius J" sort="Wagner, Claudius J" uniqKey="Wagner C" first="Claudius J" last="Wagner">Claudius J. Wagner</name><affiliation><nlm:affiliation>Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, University of Heidelberg, Heidelberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Watnick, Terry" sort="Watnick, Terry" uniqKey="Watnick T" first="Terry" last="Watnick">Terry Watnick</name><affiliation><nlm:affiliation>Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kottgen, Michael" sort="Kottgen, Michael" uniqKey="Kottgen M" first="Michael" last="Köttgen">Michael Köttgen</name><affiliation><nlm:affiliation>Renal Division, Department of Medicine, Medical Center, University of Freiburg, Freiburg, Germany. Electronic address: michael.koettgen@uniklinik-freiburg.de.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:26924047</idno><idno type="pmid">26924047</idno><idno type="doi">10.1016/j.kint.2015.11.015</idno><idno type="wicri:Area/PubMed/Corpus">000215</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000215</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Targeted rescue of a polycystic kidney disease mutation by lysosomal inhibition.</title><author><name sortKey="Hofherr, Alexis" sort="Hofherr, Alexis" uniqKey="Hofherr A" first="Alexis" last="Hofherr">Alexis Hofherr</name><affiliation><nlm:affiliation>Renal Division, Department of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. Electronic address: alexis.hofherr@uniklinik-freiburg.de.</nlm:affiliation></affiliation></author><author><name sortKey="Wagner, Claudius J" sort="Wagner, Claudius J" uniqKey="Wagner C" first="Claudius J" last="Wagner">Claudius J. Wagner</name><affiliation><nlm:affiliation>Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, University of Heidelberg, Heidelberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Watnick, Terry" sort="Watnick, Terry" uniqKey="Watnick T" first="Terry" last="Watnick">Terry Watnick</name><affiliation><nlm:affiliation>Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Kottgen, Michael" sort="Kottgen, Michael" uniqKey="Kottgen M" first="Michael" last="Köttgen">Michael Köttgen</name><affiliation><nlm:affiliation>Renal Division, Department of Medicine, Medical Center, University of Freiburg, Freiburg, Germany. Electronic address: michael.koettgen@uniklinik-freiburg.de.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Kidney international</title><idno type="eISSN">1523-1755</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antirheumatic Agents (pharmacology)</term><term>Antirheumatic Agents (therapeutic use)</term><term>Chloroquine (pharmacology)</term><term>Chloroquine (therapeutic use)</term><term>Drosophila melanogaster</term><term>Drug Evaluation, Preclinical</term><term>Female</term><term>HEK293 Cells</term><term>HeLa Cells</term><term>Humans</term><term>Lysosomes (drug effects)</term><term>Lysosomes (metabolism)</term><term>Male</term><term>Mutation, Missense</term><term>Polycystic Kidney, Autosomal Dominant (drug therapy)</term><term>Polycystic Kidney, Autosomal Dominant (genetics)</term><term>Polycystic Kidney, Autosomal Dominant (metabolism)</term><term>Protein Stability</term><term>TRPP Cation Channels (genetics)</term><term>TRPP Cation Channels (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>TRPP Cation Channels</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>TRPP Cation Channels</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antirheumatic Agents</term><term>Chloroquine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antirheumatic Agents</term><term>Chloroquine</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Lysosomes</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Polycystic Kidney, Autosomal Dominant</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Polycystic Kidney, Autosomal Dominant</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lysosomes</term><term>Polycystic Kidney, Autosomal Dominant</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Drosophila melanogaster</term><term>Drug Evaluation, Preclinical</term><term>Female</term><term>HEK293 Cells</term><term>HeLa Cells</term><term>Humans</term><term>Male</term><term>Mutation, Missense</term><term>Protein Stability</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal disease. The molecular pathogenesis of ADPKD is not completely known, and there is no approved therapy. To date, there is limited knowledge concerning the molecular consequences of specific disease-causing mutations. Here we show that the ADPKD missense variant TRPP2(D511V) greatly reduces TRPP2 protein stability, and that TRPP2(D511V) function can be rescued in vivo by small molecules targeting the TRPP2 degradation pathway. Expression of the TRPP2(D511V) protein was significantly reduced compared to wild-type TRPP2. Inhibition of lysosomal degradation of TRPP2(D511V) by the US Food and Drug Administration (FDA)-approved drug chloroquine strongly increased TRPP2 protein levels in vitro. The validation of these results in vivo requires appropriate animal models. However, there are currently no mouse models harboring human PKD2 missense mutations, and screening for chemical rescue of patient mutations in rodent models is time-consuming and expensive. Therefore, we developed a Drosophila melanogaster model expressing the ortholog of TRPP2(D511V) to test chemical rescue of mutant TRPP2 in vivo. Notably, chloroquine was sufficient to improve the phenotype of flies expressing mutant TRPP2. Thus, this proof-of-concept study highlights the potential of directed therapeutic approaches for ADPKD, and provides a rapid-throughput experimental model to screen PKD2 patient mutations and small molecules in vivo. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26924047</PMID><DateCompleted><Year>2017</Year><Month>01</Month><Day>31</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1523-1755</ISSN><JournalIssue CitedMedium="Internet"><Volume>89</Volume><Issue>4</Issue><PubDate><Year>2016</Year><Month>Apr</Month></PubDate></JournalIssue><Title>Kidney international</Title><ISOAbbreviation>Kidney Int.</ISOAbbreviation></Journal><ArticleTitle>Targeted rescue of a polycystic kidney disease mutation by lysosomal inhibition.</ArticleTitle><Pagination><MedlinePgn>949-55</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.kint.2015.11.015</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S0085-2538(15)00066-6</ELocationID><Abstract><AbstractText>Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal disease. The molecular pathogenesis of ADPKD is not completely known, and there is no approved therapy. To date, there is limited knowledge concerning the molecular consequences of specific disease-causing mutations. Here we show that the ADPKD missense variant TRPP2(D511V) greatly reduces TRPP2 protein stability, and that TRPP2(D511V) function can be rescued in vivo by small molecules targeting the TRPP2 degradation pathway. Expression of the TRPP2(D511V) protein was significantly reduced compared to wild-type TRPP2. Inhibition of lysosomal degradation of TRPP2(D511V) by the US Food and Drug Administration (FDA)-approved drug chloroquine strongly increased TRPP2 protein levels in vitro. The validation of these results in vivo requires appropriate animal models. However, there are currently no mouse models harboring human PKD2 missense mutations, and screening for chemical rescue of patient mutations in rodent models is time-consuming and expensive. Therefore, we developed a Drosophila melanogaster model expressing the ortholog of TRPP2(D511V) to test chemical rescue of mutant TRPP2 in vivo. Notably, chloroquine was sufficient to improve the phenotype of flies expressing mutant TRPP2. Thus, this proof-of-concept study highlights the potential of directed therapeutic approaches for ADPKD, and provides a rapid-throughput experimental model to screen PKD2 patient mutations and small molecules in vivo. </AbstractText><CopyrightInformation>Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Hofherr</LastName><ForeName>Alexis</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Renal Division, Department of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. Electronic address: alexis.hofherr@uniklinik-freiburg.de.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wagner</LastName><ForeName>Claudius J</ForeName><Initials>CJ</Initials><AffiliationInfo><Affiliation>Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, University of Heidelberg, Heidelberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Watnick</LastName><ForeName>Terry</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Köttgen</LastName><ForeName>Michael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Renal Division, Department of Medicine, Medical Center, University of Freiburg, Freiburg, Germany. 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